Defining and identifying early-onset lung disease in cystic fibrosis with cumulative clinical characteristics

Abstract

Background: Because of the heterogeneity in cystic fibrosis (CF) lung disease among young children, a clinical method to identify early-onset lung disease is needed.

Objective: To develop a CF early-onset lung disease (CFELD) scoring system by utilizing prospectively collected longitudinal data on manifestations in the first 3 years of life.

Design: We studied 145 infants born during 2012-2017, diagnosed through newborn screening by age 3 months, and followed to 36 months of age. Cough severity, pulmonary exacerbations (PEx), respiratory cultures, and hospitalizations were collected at each CF center visit (every 1-2 months in infancy and quarterly thereafter). These data were used to construct the CFELD system and to classify lung disease into five categories: asymptomatic, minimal, mild, moderate, and severe.

Results: The most frequent manifestation of CF early lung disease was MD-reported PEx episodes, PEx hospitalizations, and positive Pseudomonas aeruginosa cultures. Parent-reported cough severity was correlated with the number of respiratory hospitalizations (r = 0.48, p < 0.0001). The distribution of CFELD categories was 10% asymptomatic, 17% minimal, 29% mild, 33% moderate, and 12% severe. The moderate and severe categories occurred threefold higher in pancreatic insufficient (PI, 49%) versus sufficient subjects (16%), p < 0.0001. In addition to PI, gastrointestinal and nutrition-related hospitalizations, plasma cytokines interleukin (IL)-6 and IL-10, duration of CFTR modulator therapy, and type of health insurance were significant predictors of CFELD scores.

Conclusion: The CFELD scoring system is novel, allows systematic evaluation of lung disease prognosis early, and may aid in therapeutic decision-making particularly in the initiation of CFTR modulator therapy.

Keywords: Pseudomonas aeruginosa; Staphylococcus aureus; cough; cystic fibrosis; hospitalization; lung disease; pulmonary exacerbation.

FIGURE 1

Prevalence of the eight clinical manifestations (five nonhospitalization measures in (A) and three hospitalization measures in (B) used to construct the CF early-onset lung disease (CFELD) scoring system in the first year of life (1y), cumulative over 1–2 years (1–2y), and cumulative over 1–3 years (1–3y) in the FIRST cohort. The percentages of subjects who had one occurrence (1×), two occurrences (2×) and three or more occurrences (≥3×) in each manifestation are shown as open, hatched and black bars, respectively. The number inside the top black bar indicates the range of the frequency of occurrence for that manifestation. Chronic cough was defined by using cumulative cough scores indicative of having greater than occasional cough by parental report for more than 50% of time as explained in Table 2. CF, cystic fibrosis; MRSA, methicillin-resistant Staphylococcus aureus; PA, Pseudomonas aeruginosa; PEx, pulmonary exacerbation.

FIGURE 2

Correlations between MD-reported pulmonary exacerbations (PEx) and parent-reported cumulative cough scores in the first 3 years of life in the FIRST cohort. Pearson’s correlation coefficient (r) and p value are provided in each panel

FIGURE 3

Distribution of the CF early-onset lung disease (CFELD) scores and classification of the five CFELD phenotypes cumulative over the first 3 years of life: asymptomatic, minimal, mild, moderate and severe. For each CFELD score ranging from 0 to 12, the percentage of subjects that experienced at least one occurrence in each of the 8 CFELD components cumulatively by 3 years of age are visualized by horizontally stacked bars with the corresponding percentage shown underneath each bar. Chronic cough was defined by using cumulative cough scores indicative of having greater than occasional cough by parental report for more than 50% of time as explained in Table 2. CF, cystic fibrosis; MRSA, methicillin-resistant Staphylococcus aureus; PA, Pseudomonas aeruginosa; PEx, pulmonary exacerbation

FIGURE 4

Distributions of the CF early-onset lung disease (CFELD) categories by age in the first 3 years of life (A) and by pancreatic status (B) cumulative over the first 3 years of life in the FIRST cohort. CF, cystic fibrosis; MI, meconium ileus; PI, pancreatic insufficiency; PS, pancreatic sufficiency.